From owner-chemistry@ccl.net Mon Aug 24 00:22:01 2009 From: "Mannan K malie_03,,yahoo.co.in" <owner-chemistry---server.ccl.net> To: CCL Subject: CCL: How a receptor/protein is unknown in ligand based drug discovery Message-Id: <-40060-090824001851-26494-WzPAl+q2ObipMAJqZsUfWA---server.ccl.net> X-Original-From: "Mannan K" <malie_03]![yahoo.co.in> Date: Mon, 24 Aug 2009 00:18:47 -0400 Sent to CCL by: "Mannan K" [malie_03---yahoo.co.in] Hi CCLers, Often Ligand based drug discovery is known to work when there is no detail information on receptor/protein where the ligand is working. How is it possible?, If there is no information on the protein, then How can the ligands be assayed? what is the missing link? or can I assume that, the proteins are not crystallible/modelled? please clarify Mannan From owner-chemistry@ccl.net Mon Aug 24 01:44:00 2009 From: "Kalju Kahn kalju[#]chem.ucsb.edu" <owner-chemistry : server.ccl.net> To: CCL Subject: CCL: How a receptor/protein is unknown in ligand based drug discovery Message-Id: <-40061-090824013605-16199-yOKo9hHDmiGySfoE5RpwRQ : server.ccl.net> X-Original-From: "Kalju Kahn" <kalju###chem.ucsb.edu> Content-Transfer-Encoding: 8bit Content-Type: text/plain;charset=iso-8859-1 Date: Sun, 23 Aug 2009 22:35:50 -0700 MIME-Version: 1.0 Sent to CCL by: "Kalju Kahn" [kalju]_[chem.ucsb.edu] Mannan, It is more correct to say "ligand structure based" to distinguis it from "target structure based". You do not have the *structure* of the receptor, but you have some knowledge of several ligands (their structures, activities) which guide you toward discovering a better (higher affinity, more soluble ...) ligand. For example, you can develop a pharmacophore model based on known ligands, and then screen a virtual library of small moecules to identify novel structures that meet the criteria of your pharmacophore. You still do have the actual receptor in the test tube (pure or on the cell surface) so you can do assays as usual. Kalju > > Sent to CCL by: "Mannan K" [malie_03---yahoo.co.in] > Hi CCLers, > Often Ligand based drug discovery is known to work when there is no detail > information on receptor/protein where the ligand is working. > > How is it possible?, > If there is no information on the protein, then How can the ligands be > assayed? what is the missing link? > or can I assume that, the proteins are not crystallible/modelled? > > please clarify > > Mannan> > > ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Dr. Kalju Kahn Department of Chemistry and Biochemistry UC Santa Barbara, CA 93106 From owner-chemistry@ccl.net Mon Aug 24 04:30:00 2009 From: "Vincent Leroux vincent.leroux ~~ loria.fr" <owner-chemistry!A!server.ccl.net> To: CCL Subject: CCL: protein-ligand binding simulation times with molecular dynamics Message-Id: <-40062-090824032853-11193-baChLHvtvLK/L7BS2f6aEw!A!server.ccl.net> X-Original-From: Vincent Leroux <vincent.leroux.!A!.loria.fr> Content-Transfer-Encoding: 8bit Content-Type: text/plain; charset=ISO-8859-1; format=flowed Date: Mon, 24 Aug 2009 09:28:34 +0200 MIME-Version: 1.0 Sent to CCL by: Vincent Leroux [vincent.leroux|loria.fr] Hi Andrew, The answer to your question really depends on your target, so the more prior knowledge about it the better. 1 ns should be enough for a rigid hydrophobic receptor. With a flexible, solvent-accessible receptor, you could need more simulation time, not more than 10 ns, and IMO 5 is enough for a small ligand... But if you are simulating a target for which solvent effects could play a key role in ligand binding I would consider explicit solvent prior to extending the simulation time. I have had the case of a ligand that was promising according to docking, very stable upon MD in vacuo or with implicit solvent (10 ns), and unstable after 1 ns when the complex was put in the middle of a 80x80x80 TIP3 water box (2 ns were done). The ligand was not potent experimentally... In any case, as Florent said, spotting RMSD variations of the ligand is a good and simple way to decide whether or not the MD simulation should be extended. Regards, VL Andrew Voronkov drugdesign[-]yandex.ru a �crit : > Sent to CCL by: Andrew Voronkov [drugdesign[*]yandex.ru] > Dear CCl users, > How much time it will take to assess organic compound's binding with Mw=300-400 to the protein's potential binding site with molecular dynamics? Is 1-5 nanoseconds enough? > The goal is to assess the stability of protein-ligand complex and then to evaluate its stability by MM-PBSA for selection from ligands databases? > > Best regards, > Andrew > From owner-chemistry@ccl.net Mon Aug 24 04:53:01 2009 From: "Jens Spanget-Larsen spanget%%ruc.dk" <owner-chemistry|*|server.ccl.net> To: CCL Subject: CCL:G: TDDFT problem Message-Id: <-40063-090824041630-3466-u3mJlqaW0h+vwaGqKTlRPA|*|server.ccl.net> X-Original-From: Jens Spanget-Larsen <spanget(~)ruc.dk> Content-Transfer-Encoding: 7bit Content-Type: text/plain; charset=ISO-8859-1; format=flowed Date: Mon, 24 Aug 2009 09:43:50 +0200 MIME-Version: 1.0 Sent to CCL by: Jens Spanget-Larsen [spanget.:.ruc.dk] Dear Tom, for what it is worth, I can provide this information. For a small organic compound (22 atoms, C2v symmetry) I observed the following cpu times on our modest campus cluster: 15 states (conver=3), cpu = 2 h 100 states (conver=2), cpu = 16 h 150 states (conver=2), cpu = 21 h These calculations were all started from scratch, but you may build up the calculation gradually by using the 'add' option, adding mor and more states. Jens >--< ------------------------------------------------------ JENS SPANGET-LARSEN Office: +45 4674 2710 Dept. of Science (18.1) Fax: +45 4674 3011 Roskilde University Mobile: +45 2320 6246 P.O.Box 260 E-Mail: spanget .. ruc.dk DK-4000 Roskilde, Denmark http://www.ruc.dk/~spanget ------------------------------------------------------ Tom de Greef t.f.a.d.greef. .. .tue.nl wrote: > Sent to CCL by: "Tom de Greef" [t.f.a.d.greef#%#tue.nl] > Dear all, > > Recently, I have run into some problems with TD-DFT calculations using the Gaussian 03 program. > I have optimized a molecule of around 132 atoms, of which half are carbons, nitrogens and oxygen atoms. Optmization and frequency analysis revealed that the molecule has been optmized properly (no imaginary frequencies). Now I would like to calculate the vertical excitations using TD-DFT. However, when I use TDDFT with td=(nstates=30,root=1) almost all my oscillator strengths are close to zero. > My first question is, is there a way in which I can tell Gaussian to skip finding states of which the oscillator strength is almost zero? My second question relates to time issues. Does anyone know how my calculation time scales with the number of states I am interested in? I use the PBE0 functional and a 6-31G+(d,p) basis set. How much additional time would it take to find lets say 50 states? > Thank you for your help. > > Best regards, > > Tom> > > From owner-chemistry@ccl.net Mon Aug 24 10:43:00 2009 From: "Gary Breton gbreton^berry.edu" <owner-chemistry##server.ccl.net> To: CCL Subject: CCL: How a receptor/protein is unknown in ligand based drug discovery Message-Id: <-40064-090824103541-6560-ht0dyurEnJR2VyPJHQunJw##server.ccl.net> X-Original-From: Gary Breton <gbreton]^[berry.edu> Content-transfer-encoding: 7bit Content-type: text/plain; charset="US-ASCII" Date: Mon, 24 Aug 2009 10:00:41 -0400 Mime-version: 1.0 Sent to CCL by: Gary Breton [gbreton:berry.edu] A receptor site predictor such as Q-SiteFinder can provide some probable/potential binding sites and start as a searching point for a protein without any prior crystal structure data concerning protein-ligand interactions: http://www.modelling.leeds.ac.uk/qsitefinder/ Gary Breton On 8/24/09 12:18 AM, "Mannan K malie_03,,yahoo.co.in" <owner-chemistry\a/ccl.net> wrote: > > Sent to CCL by: "Mannan K" [malie_03---yahoo.co.in] > Hi CCLers, > Often Ligand based drug discovery is known to work when there is no detail > information on receptor/protein where the ligand is working. > > How is it possible?, > If there is no information on the protein, then How can the ligands be > assayed? what is the missing link? > or can I assume that, the proteins are not crystallible/modelled? > > please clarify > > Mannan> > From owner-chemistry@ccl.net Mon Aug 24 11:42:01 2009 From: "Vincent Leroux vincent.leroux(-)loria.fr" <owner-chemistry*_*server.ccl.net> To: CCL Subject: CCL: How a receptor/protein is unknown in ligand based drug discovery Message-Id: <-40065-090824041640-3522-cIJXanajna8XTEPZRTYTjQ*_*server.ccl.net> X-Original-From: Vincent Leroux <vincent.leroux_-_loria.fr> Content-Transfer-Encoding: 8bit Content-Type: text/plain; charset=ISO-8859-1; format=flowed Date: Mon, 24 Aug 2009 10:16:22 +0200 MIME-Version: 1.0 Sent to CCL by: Vincent Leroux [vincent.leroux===loria.fr] Hi Mannan, Ligand-based drug design is based on the hypothesis that the binding strength of a given compound is related somewhat to a feature that can be known simply from the compound's properties. So if you have a large set of compounds for which you know the potency, a statistical analysis of all that data might suggest you interesting optimizations. The classical empirical approach. "Dirty" from a theoretical point of view, but it makes sense. It all depends on the accuracy of the reference data, and the amount that is required so that the SAR relationships will get clear... This approach is more popular (and more efficient) in the pharmas than structure-based/receptor-based drug design because they can screen large compound databases experimentally, and because the statistical methods can be useful not only for predicting potency but also for other crucial aspects of drug design such as specificity, toxicity, availability, all of which are mostly out of reach from the theoretical methods... Do not forget that structure-based drug design simply will probably never work in many cases, and not only when the target structure is unknown. A good example is Gleevec development. Optimizations based on computer modeling all failed in that case, and no one understood why, until crytallography eventually revealed that the compound (successfully optimized using classical medicinal chemistry) was not binding to the Abl kinase exactly like ATP does to all kinases... Regards, VL Mannan K malie_03,,yahoo.co.in a �crit : > Sent to CCL by: "Mannan K" [malie_03---yahoo.co.in] > Hi CCLers, > Often Ligand based drug discovery is known to work when there is no detail information on receptor/protein where the ligand is working. > > How is it possible?, > If there is no information on the protein, then How can the ligands be assayed? what is the missing link? > or can I assume that, the proteins are not crystallible/modelled? > > please clarify > > Mannan > >